PROJECT SUMMARY. Effective responses in Fc-dependent, antibody-mediated killing for therapeutic ablation require efficient and productive interactions between the cell-type specific Fc receptors of the host and the therapeutic monoclonal antibody. The lack of effective responses in many patients, perhaps as much as 30%, represents both an opportunity and a challenge to delineate the mechanistic basis for such differences. Genetic inquiry can identify the contributions that the host brings to these differences. Our preliminary data indicate that nearly one-third of persons have structural variants (SV) in the classical Fc locus in addition to the prevalent single nucleotide polymorphisms affecting affinity of ligand binding, receptor mobility in the plane of the cell membrane and quantitative receptor expression. These larger structural variants affect Fc receptors on both lymphoid and myeloid cell series, and nearly a third of these variants are uncharacterized in terms of genomic structure, resultant alterations in protein structure and impact on net biological function. New, innovative technical approaches including linked-reads sequencing, now confirmed with conventional PCR, have demonstrated novel structures in genomic organization. Application of CRISPR/Cas9 targeted excision of the locus, coupled with linked-reads sequencing now enables resolution of novel structural variations impacting biological function. Coupled with the potential to enhance expression of key activating receptors, there is the exceptional opportunity to enhance both the host response to therapeutic mAbs but also to vaccination protocols. Accordingly, the aims of this proposal are 1) enabled by our characterized cohort of donors (N > 5,000) with different ancestral backgrounds, to characterize the genomic organization of novel structural variants using linked-read, locus specific excision and long read strategies; 2) to identify the predicted novel receptor proteins and their structures and assess their expression and function, including possible decoy, signaling deficient structures; and 3) to develop a scalable, generalizable platform to assess the repertoire of SNPs and larger genomic structural variants in the human FCGR genetic locus to understand the population diversity in our expanding donor pool (>10,000) and assess the ability to predict response to therapeutic antibody therapy. Assessment of the portfolio of receptors, their structures and their expression will enable strategies for selection and stratification of recipients for an optimal precision medicine approach.